Ubiquitination is a reversible, covalent post-translational modification that regulates
protein function and as such plays crucial roles in a wide range of physiological
processes. Importantly, gain- or loss-of-function mutations in components of the
ubiquitin system have been causally linked to tumorigenesis. The reverse reaction of
ubiquitination is catalyzed by deubiquitinases (DUBs), a family of enzymes that
removes ubiquitin from proteins.
BRCA1-Associated Protein 1 (BAP1) is a deubiquitinase known to be a tumor
suppressor and anti-metastatic protein since deletions and rearrangements are observed
in a wide range of tumors. However, little is known about how BAP1 works into the
cells. Here, we show that BAP1 is hyperphosphorylated after DNA damage by gamma
radiations and ultraviolet light, probably by ATM and/or ATR. Moreover, we found that
BAP1 depletion cause a defect in the maintenance of the G2/M checkpoint after gamma
radiation, suggesting that BAP1 is required to maintain the arrest after DNA damage.
This delay is important to allow DNA repair and to prevent genomic instability.
Consistently, we found that BAP1 expression in BAP1 deficient cells restore normal
diploidy and prevent nuclear aberrations, suggesting that BAP1 links DNA damage
induced checkpoint regulation to genomic stability: two important processes for
carcinogenesis.
These findings provide new insights into the role of deubiquitination in cell signaling
and neoplastic transformation.